RESUMEN

Behçet disease is a multi-system disease associated with human leukocyte antigen (HLA) class I polymorphism. High-resolution next-generation sequencing (NGS) with haplotype analysis has not been performed previously for this disease. Sixty Egyptian patients diagnosed according to the International Study Group (ISG) criteria for Behçet disease and 160 healthy geographic and ethnic-matched controls were genotyped for HLA class I loci (HLA-A, B, C). For HLA class II loci (DRB1, DRB3/4/5, DQA1, DQB1, DPA1, DPB1), 40 control samples were genotyped. High-resolution HLA genotyping was performed using NGS and the results were analyzed. Clinical manifestations were oral ulcers (100%), genital ulcers (100%), eye (55%) and neurological (28%) and vascular involvement (35%). HLA-B*51:08 [odds ratio (OR) = 19·75, 95% confidence interval (CI) = 6·5-79; P < 0·0001], HLA-B*15:03 (OR = 12·15, 95% CI = 3·7-50·7; P < 0·0001), HLA-C*16:02 (OR = 6·53, 95% CI = 3-14; P < 0·0001), HLA-A*68:02 (OR = 3·14, 95% CI = 1·1-8·9; P < 0·01) were found to be associated with Behçet disease, as were HLA-DRB1*13:01 and HLA-DQB1*06:03 (OR = 3·39, 95% CI = 0·9-18·9; P = 0·04 for both). By contrast, HLA-A*03:01 (OR = 0·13, 95% CI = 0-0·8; P = 0·01) and HLA-DPB1*17:01 were found to be protective (OR = 0·27, 95% CI = 0·06-1·03; P = 0·02). We identified strong linkage disequilibrium between HLA-B*51:08 and C*16:02 and A*02:01 in a haplotype associated with Behçet disease. HLA-B*51:08 was significantly associated with legal blindness (OR = 2·98, 95% CI = 1·06-8·3; P = 0·01). In Egyptian Behçet patients, HLA-B*51:08 is the most common susceptibility allele and holds poor prognosis for eye involvement.

Asunto(s)

Síndrome de Behçet/genética , Antígenos HLA/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Antígenos HLA-D/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Adulto , Alelos , Síndrome de Behçet/patología , Egipto , Femenino , Frecuencia de los Genes , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético

RESUMEN

HLA-A, -B and -C alleles of 285 individuals, representing three Iranian Lur populations and one Iranian Kurd population were sequenced completely, yielding human leukocyte antigen (HLA) class I genotypes at high resolution and filling four fields of the official HLA nomenclature. Each population has 87-99 alleles, evenly distributed between the three HLA class I genes, 145 alleles being identified in total. These alleles were already known, named and deposited in the HLA database. The alleles form 316 different HLA A-B-C haplotypes, with each population having between 80 and 112 haplotypes. The four Iranian populations form a related group that is distinguished from other populations, including other Iranians. All four KIR ligands - the A3/11, Bw4, C1 and C2 epitopes - are well represented, particularly Bw4, which is carried by three high-frequency allotypes: HLA-A*24:02, HLA-A*32:01 and HLA-B*51:01. In the Lur and Kurd populations, between 82% and 94% of individuals have the Bw4 epitope, the ligand for KIR3DL1. HLA-B*51:01 is likely of Neandertal origin and associated with Behcet's disease, also known as the Silk Road disease. The Lordegan Lur have the highest frequency of HLA-B*51:01 in the world. This allele is present on 46 Lur and Kurd haplotypes. Present at lower frequency is HLA-B*51:08, which is also associated with Behcet's disease. In the four Iranian populations, 31 haplotypes encode both Bw4(+) HLA-A and Bw4(+) HLA-B, a dual combination of Bw4 epitopes that is relatively rare in other populations, worldwide. This study both demonstrates and emphasizes the value of studying HLA class I polymorphism at highest resolution in anthropologically well-defined populations.

Asunto(s)

Etnicidad , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Polimorfismo Genético , Receptores KIR/genética , Alelos , Bases de Datos Genéticas , Epítopos/química , Epítopos/inmunología , Expresión Génica , Frecuencia de los Genes , Genotipo , Antígenos HLA-A/clasificación , Antígenos HLA-A/inmunología , Antígenos HLA-B/clasificación , Antígenos HLA-B/inmunología , Antígenos HLA-C/clasificación , Antígenos HLA-C/inmunología , Haplotipos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Irán , Ligandos , Receptores KIR/clasificación , Receptores KIR/inmunología , Análisis de Secuencia de ADN , Terminología como Asunto

RESUMEN

A newly identified allele of the KIR2DL4 natural killer cell receptor for human leukocyte antigen (HLA) class I.

Asunto(s)

Alelos , Exones , Mutación Puntual , Receptores KIR2DL4/genética , Sustitución de Aminoácidos , Secuencia de Bases , Codón , Haplotipos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Células Asesinas Naturales/citología , Células Asesinas Naturales/inmunología , Tipificación Molecular , Receptores KIR2DL4/inmunología , Alineación de Secuencia , Análisis de Secuencia de ADN

RESUMEN

Natural killer (NK) cells are a population of lymphocytes that function in both immune defense and reproduction. Diversifying NK cell phenotype and function are interactions between NK cell receptors and major histocompatibility complex (MHC) class I ligands. As a consequence of strong and variable selection these ligand-receptor systems are polymorphic, rapidly evolving, and considerably species-specific. Counterparts to the human system of HLA class I ligands and killer cell immunoglobulin-like receptors (KIR) are present only in apes and Old World monkeys. HLA-C, the dominant ligand for human KIR and the only polymorphic HLA class I expressed by trophoblast, is further restricted to humans and great apes. Even then, the human system appears qualitatively different from that of chimpanzees, in that it has evolved a genetic balance between particular groups of receptors and ligands that favor reproductive success and other groups of receptors and ligands that have been correlated with disordered placentation. Human populations that have survived successive episodes of epidemic disease and population bottlenecks maintain a breadth of diversity for KIR and HLA class I, implying that loss of such diversity disfavors long-term survival of a human population.

Asunto(s)

Fenómenos Inmunogenéticos , Placentación , Embarazo/inmunología , Animales , Femenino , Regulación del Desarrollo de la Expresión Génica , Genes MHC Clase I , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Placenta/citología , Placenta/inmunología , Placenta/metabolismo , Embarazo/metabolismo , Proteínas Gestacionales/genética , Proteínas Gestacionales/metabolismo , Receptores KIR/genética , Receptores KIR/metabolismo , Útero/citología , Útero/inmunología , Útero/metabolismo

RESUMEN

Analysis of FcgammaRIIA alleles in Pakistanis and in Trinidadians of South Asian, African and mixed ancestry revealed no significant differences between Trinidadian South Asians and Pakistanis. H131 homozygotes were more common among Trinidadian South Asians than among Africans and those of mixed ancestry. Comparison with other populations revealed east-west geographic gradients of allele frequencies.

Asunto(s)

Antígenos CD/genética , Polimorfismo Genético , Receptores de IgG/genética , África , Asia , Frecuencia de los Genes , Humanos

RESUMEN

Coeliac disease is strongly heritable, with more than half of the genetic susceptibility estimated to come from genes outside the HLA region. Several candidate regions have been suggested from genome-wide linkage studies including chromosome 19q13.4 where linkage has been replicated between populations. The natural killer (NK) cell immunoglobulin-like receptors (KIRs) and leukocyte immunoglobulin-like receptor (LILR, also known as ILT and LIR) gene clusters lie within this region in the leukocyte receptor cluster (LRC). KIR molecules are involved in cytotoxic lymphocyte function and expressed by intraepithelial T and NK cells in the duodenum. We studied 132 unrelated UK Caucasian coeliac patients and their parents together with a control group of 171 UK Caucasians. PCR-SSP for KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL5, LILRA3 (ILT6), LILRA3 deletion and an LILRA3 exon 3 single nucleotide polymorphism (SNP) allowed classification of KIR genotypes into five categories and determination of homozygosity or heterozygosity for the common A and B type KIR haplotypes (as defined in the text) and for the LILRA3 deletion. Case-control analysis found no association of the five KIR genotype categories, the A or B KIR haplotypes, the LILRA3 gene deletion or the LILRA3 exon 3 SNP with coeliac disease. A transmission disequilibrium test also found no association of the A and B KIR haplotypes or the LILRA3 gene deletion with coeliac disease.

Asunto(s)

Enfermedad Celíaca/genética , Cromosomas Humanos Par 19 , Predisposición Genética a la Enfermedad , Receptores Inmunológicos/genética , Estudios de Casos y Controles , Humanos , Familia de Multigenes , Receptores KIR , Receptores KIR2DL1 , Receptores KIR2DL2 , Receptores KIR2DL3

RESUMEN

Lymphocyte subpopulation levels are used for prognosis and monitoring of a variety of human diseases, especially those with an infectious etiology. As a primary step to defining the major gene variation underlying these phenotypes, we conducted the first whole-genome screen for quantitative variation in lymphocyte count, CD4 T cell, CD8 T cell, B cell, and natural killer cell numbers, as well as CD4:CD8 ratio. The screen was performed in 15 of the CEPH families that form the main human genome genetic project mapping resource. Quantitative-trait loci (QTLs) that account for significant proportions of the phenotypic variance of lymphocyte subpopulations were detected on chromosomes 1, 2, 3, 4, 8, 9, 11, 12, and 18. The most significant QTL found was for CD4 levels on chromosome 8 (empirical P=.00005). Two regions of chromosome 4 showed significant linkage to CD4:CD8 ratio (empirical P=.00007 and P=.003). A QTL for the highly correlated measures of CD4 and CD19 levels colocalized at 18q21 (both P=.003). Similarly, a shared region of chromosome 1 was linked to CD8 and CD19 levels (P=.0001 and P=.002, respectively). Several of the identified chromosome regions are likely to harbor polymorphic candidate genes responsible for these important human phenotypes. Their discovery has important implications for understanding the generation of the immune repertoire and understanding immune-system homeostasis. More generally, these data show the power of an integrated human gene-mapping approach for heritable molecular phenotypes, using large pedigrees that have been extensively genotyped.

Asunto(s)

Linfocitos B/metabolismo , Cromosomas Humanos/genética , Subgrupos Linfocitarios/metabolismo , Carácter Cuantitativo Heredable , Linfocitos T/metabolismo , Alelos , Antígenos CD/análisis , Linfocitos B/citología , Mapeo Cromosómico , Femenino , Citometría de Flujo , Genes bcl-2/genética , Humanos , Células Asesinas Naturales/citología , Células Asesinas Naturales/metabolismo , Desequilibrio de Ligamiento , Recuento de Linfocitos , Subgrupos Linfocitarios/citología , Masculino , Fenotipo , Linfocitos T/citología , Utah

RESUMEN

Natural killer (NK) and some T cells express killer cell immunoglobulin-like receptors (KIRs), which interact with HLA class I expressed by target cells and consequently regulate cytolytic activity. The number of KIR loci can vary and so a range of genetic profiles is observed. We have determined the KIR genetic profiles from one African (n = 62) and two South Asian (n = 108, n = 78) populations. Several of the KIRs are present at significantly different frequencies between the two major ethnic groups (eg KIR2DS4 gene frequency 0.82 African, 0.47 S Asian. Pc < 1 x 10(-6)) and this is due to uneven distribution of two KIR haplotype families 'A' and 'B'. All three populations described here displayed a greater degree of diversity of KIR genetic profiles than other populations investigated, which indicates further complexity of underlying haplotypes; in this respect we describe two individuals who appear homozygous for a large deletion including the previously ubiquitous 2DL4. We have also reanalysed three populations that we studied previously, for the presence of a KIR which is now known to be an indicator of the 'B' haplotype. South Asians had the highest overall frequencies of all KIR loci characteristic of 'B' haplotypes (Pc < 0.0001 to < 0.004). Furthermore, gene frequency independent deviances in the linkage disequilibrium were apparent between populations.

Asunto(s)

Receptores Inmunológicos/genética , África Occidental , Bangladesh , Frecuencia de los Genes , Haplotipos , Humanos , India , Células Asesinas Naturales/inmunología , Desequilibrio de Ligamiento , Pakistán , Receptores KIR , Receptores KIR2DL4 , Trinidad y Tobago/etnología

RESUMEN

Natural killer (NK) and some T cells express killer cell immunoglobulin-like receptors (KIRs), which interact with HLA class I expressed by target cells and consequently regulate cytolytic activity. The number of KIR loci can vary and so a range of genetic profiles is observed. We have determined the KIR genetic profiles from one African (n = 62) and two South Asian (n = 108, n = 78) populations. Several of the KIRs are present at significantly different frequencies between the two major ethnic groups (eg KIR2DS4 gene frequency 0.82 African, 0.47 S Asian. Pc < 1 x 10(-6)) and this is due to uneven distribution of two KIR haplotype families 'A' and 'B'. All three populations described here displayed a greater degree of diversity of KIR genetic profiles than other populations investigated, which indicates further complexity of underlying haplotypes; in this respect we describe two individuals who appear homozygous for a large deletion including the previously ubiquitous 2DL4. We have also reanalysed three populations that we studied previously, for the presence of a KIR which is now known to be an indicator of the 'B' haplotype. South Asians had the highest overall frequencies of all KIR loci characteristic of 'B' haplotypes (Pc < 0.0001 to < 0.004). Furthermore, gene frequency independent deviances in the linkage disequilibrium were apparent between populations.

Asunto(s)

Humanos , Estudio Comparativo , Research Support, Non-U.S. Gov't , África Occidental , Bangladesh , Frecuencia de los Genes , India , Pakistán , Receptores Inmunológicos/genética , Trinidad y Tobago/epidemiología , Haplotipos , Células Asesinas Naturales/inmunología , Desequilibrio de Ligamiento

RESUMEN

Killer cell immunoglobulin-like receptors (KIRs) are members of a group of molecules that specifically recognize HLA class I ligands and are found on subsets of human lymphopoetic cells. The number of KIR loci can vary between individuals, resulting in a heterogeneous array of possible KIR genes. The range of observed profiles has been explained by the occurrence of two haplotype families termed A and B which can be distinguished on the basis of certain KIR sequences. Here we attempted to determine whether the frequencies of putative KIR loci and the two haplotype groups vary in three ethnically defined, healthy, and unrelated control populations, namely UK Caucasoid (n=136), Palestinian (n=105) and Thai (n=119). We molecularly typed genomic DNA for the presence of 12 putative KIR loci, KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR3DL1, KIR3DL2, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, and KIR3DS1, using modified PCR sequence-specific primers. The patterns of KIR locus frequencies combined with the similar linkage disequilibrium values suggest that there was a distinction in the distribution of the two broad haplotype groups between the populations studied. The A haplotype was always the most prevalent, but the ratio of A to B varied between populations. The frequency of B haplotype was highest in the Palestinians and lowest in the Thais (Pc<0.0001).

Asunto(s)

Etnicidad/genética , Inmunoglobulinas/química , Células Asesinas Naturales/metabolismo , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Alelos , Árabes/genética , Pueblo Asiatico/genética , Cartilla de ADN/genética , Frecuencia de los Genes , Marcadores Genéticos , Variación Genética , Haplotipos/genética , Humanos , Ligandos , Desequilibrio de Ligamiento , Reacción en Cadena de la Polimerasa , Receptores de Superficie Celular/química , Tailandia/etnología , Reino Unido , Población Blanca/genética

Asunto(s)

Rechazo de Injerto/diagnóstico , Supervivencia de Injerto/inmunología , Antígenos HLA/inmunología , Inmunoglobulina G/sangre , Isoanticuerpos/sangre , Trasplante de Riñón/inmunología , Adulto , Linfocitos B/inmunología , Estudios de Seguimiento , Rechazo de Injerto/sangre , Rechazo de Injerto/inmunología , Humanos , Sensibilidad y Especificidad , Factores de Tiempo , Trasplante Homólogo